UT Biological Sciences Faculty Research - Dr. Lirim Shemshedini

Lirim Shemshedini

Research

The growth and progression of prostate cancer are dependent on androgens and the androgen
receptor (AR). Androgens and AR act in cells by modulating gene expression. Our lab
has two major research interests: i) proteins that regulate AR transcriptional activity
and ii) AR-regulated gene expression. On the first interest, we have studied for many
years the role of the proto-oncoprotein c-Jun as a coactivator of AR. Our data show
that c-Jun coactivation regulates androgen-dependent proliferation of and androgen-induced
gene expression in prostate cancer cells. Indeed, the growth of both androgen-dependent
and –independent prostate cancer cells is compromised by down-regulation of c-Jun
activity. In addition, our lab has studied the inhibitory activities on AR of c-Fos,
the dimerization partner of c-Jun, and p53, a tumor suppressor that is a common target
of mutational disruption in cancer. More recently, we have analyzed the role of sumoylation
in regulating AR activity. These studies led to the discovery that SUMO-3, a protein
that is conjugated to target proteins by sumoylation, can strongly enhance AR transcriptional
activity independent of its sumoylation function.

With respect to the second research interest, we have identified several novel androgen-regulated
genes through gene expression profiling studies in LNCaP cells, which are sensitive
to the pro-carcinogenic effects of androgens. Among several genes that we are currently
studying, our major focus is on two genes, sGC1 and ETV1. sGC1 is a component of soluble guanylyl cyclase (sGC), the enzyme that mediates the widespread
cellular effects of the important signaling molecule nitric oxide (NO). Our data show
that sGC1 expression increases substantially with increasing stage of prostate cancer and
that sGC1 mediates androgen-dependent and androgen–independent prostate cancer cell proliferation.
More evidence strongly suggests that sGC1 is having this proliferative effect independent of sGC1, NO, and cGMP, and PKG, opening the possibility of a novel signaling pathway by
which sGC1 is affecting cells. The other gene, ETV1, encodes an Ets transcription factor. It
was recently reported that TMPRSS2, an AR-regulated gene, was reported to fuse to
the ETV1 gene in a subset of prostate cancers, suggesting an important role for ETV1
in prostate cancer. Our data strongly suggest that AR enhances the invasion capacity
of prostate cancer cells by inducing the expression of ETV1, which can regulate the
expression of, among several genes, MMP genes. These data, together with increased
expression of ETV1 in prostate tumors, led us to hypothesize that ETV1 is an AR-regulated
gene that mediates the pro-invasive effect of AR in prostate cancer. sGC1 and ETV1 provide two novel androgen-regulated genes that may be mediating the proliferative
and invasive, respectively, activities of AR in prostate cancer.